Pramlintide

1. 01Skin

   Injected under the skin before a meal

   The medicine is a small protein, so it cannot be swallowed. It is injected into the fat under the skin and slips into the blood within minutes.

   For experts

   Given by subcutaneous injection; absolute bioavailability is about 30-40% and mean time to peak plasma concentration is roughly 19-21 minutes across studied doses. Peptides of this size are not orally bioavailable.[src]

2. 02Bloodstream

   Acts quickly and is cleared quickly

   Pramlintide does not last long in the blood. Half of it is gone in under an hour, so its effect is short and centred on the meal it is given with.

   For experts

   Elimination half-life is about 48 minutes in healthy people; about 40% is unbound in plasma, and it does not bind extensively to red cells or albumin. The main metabolite, des-Lys1 pramlintide (2-37), is active in vitro. No bioaccumulation was seen with repeat dosing.[src]

3. 03Stomach

   Slows how fast food leaves the stomach

   Food moves into the gut more slowly, so sugar from a meal enters the blood more gradually instead of in a rush.

   For experts

   In men with type 1 diabetes, pramlintide delayed gastric emptying of both the solid and liquid parts of a test meal (median solid lag time 150 vs 44.5 minutes with placebo during infusion), and subcutaneous single doses delayed solid emptying of the first meal but not of a second meal four hours later. The label states amylin slows gastric emptying without altering overall nutrient absorption.[src][src][src]

4. 04Pancreas

   Turns down the sugar-raising hormone glucagon

   After a meal, people with diabetes often make too much glucagon, a hormone that tells the body to put out more sugar. In studies, pramlintide stopped or reduced that after-meal jump.

   For experts

   Postprandial glucagon rose after a meal on placebo but not on pramlintide in people with type 1 diabetes (a crossover intravenous-infusion study and a 14-day injection study), and was reduced during intravenous infusion in insulin-treated and non-insulin-treated people with type 2 diabetes. The authors concluded this likely contributes to the lower postprandial glucose; the exact cellular pathway in humans is not settled by these studies.[src][src]

5. 05Brain

   Signals fullness in the brain

   Amylin also talks to a part of the brainstem that helps end a meal. In people, one dose given before a small meal made them eat less at a buffet an hour later. The detailed brain circuit has been worked out in animals (mainly rats), not in people.

   For experts

   Animal-only evidence (rodent studies, mainly rats): amylin acts directly at the area postrema through calcitonin receptor/RAMP heterodimers, activating noradrenergic neurons there and pathways to the nucleus of the solitary tract and lateral parabrachial nucleus. Human evidence: in a crossover study, a single pramlintide injection before a preload meal reduced energy intake at an ad libitum buffet 1 hour later by 23% in insulin-treated men with type 2 diabetes and 16% in obese men without diabetes, without changing meal duration; the brain site of action in humans was not measured.[src][src]

6. 06Bloodstream

   Smaller sugar spikes after meals

   Together these effects flatten the sugar spike after eating. In year-long trials, adding pramlintide to insulin lowered long-term blood sugar a little and people gained less weight or lost a small amount.

   For experts

   Adding pramlintide to mealtime insulin lowered HbA1c in type 1 diabetes (-0.29% and -0.34% vs -0.04% with placebo at 52 weeks, with weight change -0.4 kg vs +0.8 kg) and in type 2 diabetes (-0.62% from baseline at 52 weeks with the highest regimen studied, significantly more than placebo, with -1.4 kg vs +0.7 kg on placebo). Severe hypoglycaemia risk is increased when used with insulin, which is why the label has a boxed warning.[src][src][src]

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